With the recent development of molecularly-targeted oncoprotein inhibitor drugs, the field of oncology is finally moving towards cancer treatment based on genetic mutations. BRAFV600E inhibitors (BRAFi) have revolutionized treatment for metastatic melanoma, although adaptive resistance occurs almost universally in patients. Fortunately, FDA-approved negative checkpoint blockade immunotherapies are now also widely used in the clinic. Despite an exciting and rapid push to combine immunotherapies and oncoprotein inhibitors in cancer patients, much of the basic biological understanding of how anti-tumor immunity and oncogenic pathways interact remains lacking. Our published work demonstrates that short-term BRAF-inhibition in mice bearing autochthonous melanoma, impairs MDSC accumulation in the tumor microenvironment, however the immunosuppressive characteristics of tumors approaching resistance to BRAFi have remained undefined. Herein we describe a novel model of acquired in vivo resistance to BRAFi, and show that BRAFi-resistant melanomas exhibit total restoration of the immunosuppressive myeloid cell compartment prior to their aggressive outgrowth. Whether MDSCs themselves promote BRAFi-resistance, and how their presence affects tumor responsiveness to immunotherapy remains unknown. Our preliminary data further show that dual checkpoint blockade immunotherapy (anti-CTLA-4 + anti-PD-1) can significantly delay the out-growth of BRAFi-resistant variants, but that this effect is minor. Thus the optimal timing for administering checkpoint blockade immunotherapy in relation to MDSC repopulation is not known. Based on these findings, we hypothesize that immunosuppressive myeloid cell repopulation of BRAFi-resistant melanomas is a significant obstacle to effective anti-tumor immunity, but that properly-timed depletion of MDSCs, in conjunction with immunotherapy, will greatly facilitate the treatment of BRAFi-resistant melanomas. Specific Aim 1 will determine how immunosuppressive myeloid cells influence tumor resistance to BRAF-inhibitors. We will deplete myeloid cell subsets, or block their recruitment to the tumor microenvironment, to study how T cell immunity, tumor progression, and tumor mutational load, are affected in BRAFi-resistant tumors. MDSCs are expected to be key facilitators of resistant tumor outgrowth. Specific Aim 2 will determine how immunotherapy can be optimally employed in the setting of BRAFi-resistance. We will administer checkpoint blockade immunotherapy in conjunction with MDSC depletion/blockade (as defined in Aim 1) to understand the requirements for effective immunotherapy of BRAFi-resistant melanomas. Studies will define how anti-tumor T cell responses can restrict the progression of BRAFi-escape variants. Our findings are expected to define how host anti-tumor immunity can optimally function in the setting of drug resistance.